1. Field of the Invention
This invention relates to 4-(S)-8-(.omega.-carboxy-1-oxoalkylamino) derivatives of sorbinil useful as ligands for affinity chromatographic purification of aldose reductase; to use of the derivatives and to methods for their preparation.
2. Description of Related Art
While the search for improved oral antidiabetic agents continues, considerable effort is currently directed to the discovery of compounds of value in preventing or minimizing certain chronic complications of diabetes such as cataract formation, neuropathy, nephropathy and retinopathy. Such compounds function as inhibitors of the enzyme aldose reductase which is primarily responsible for regulating the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidney of various diabetic subjects are thereby prevented or otherwise reduced as the case may be. As a result, such compounds are definitely of value as aldose reductase inhibitors for controlling certain chronic diabetic complications, including those of an ocular nature, since it is already known in the art that the presence of polyols in the lens of the eye invariably leads to cataract formation together with a concomitant loss of lens clarity.
The availability of high quality aldose reductase is important for the above-mentioned effort since the activity of compounds as agents for control of chronic diabetic complications is determined by measuring their ability to inhibit the activity of isolated aldose reductase [C. A. Lipinski et al., Ann. Reports Med. Chem. 19, 169 (1984)].
Crabbe et al., Biochem. Soc. Trans. 8, 194 (1980) report the purification of aldose reductase from bovine lens by means of poly[2-(diethylamino)ethyl]polyglycerylene dextran hydrochloride (DEAE-Sephadex, available from Pharmacia Fine Chemicals, Uppsala, Sweden) and affinity chromatography on cyclic AMP-Sepharose (also available from Pharmacia Fine Chemicals).
Purification of pre-purified porcine lens aldose reductase by affinity chromatography by a factor of 3.times. based on specific activity was reported by Branlant [Eur. J. Biochem. 129 99 (1982)].
Sorbinil, the USAN name for 2,3-dihydro-6-fluoro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione , and its use for the control (therapeutic and prophylactic) of diabetes-associated chronic complications are disclosed in U.S. Pat. Nos. 4,130,714 and 4,147,795.
The 8-nitro- and 8-amino derivatives of sorbinil are described in U.S. Pat. No. 4,248,882, issued Feb. 3, 1981.
Hasler et al., Med. Chem. Symp., Cambridge, England, disclose a series of 8-[(substituted aminorbonyl)amino]-2 3-dihydro-6-fluoro-spiro-chromane- 4,5-thiazolidine-2',4'-diones as aldose reductase inhibitors.